Wei et al. Exp Hematol Oncol (2017) 6:16 DOI 10.1186/s40164-017-0076-3
Experimental Hematology & Oncology Open Access
RESEARCH
Clinical implications of c‑maf expression in plasma cells from patients with multiple myeloma GuoQing Wei1, LiJun Wang2, HanJin Yang2, XiaoYan Han1, GaoFeng Zheng1, WeiYan Zheng1, Jie Sun1, JiMin Shi1, WenJun Wu1, Yi Zhao1, DongHua He1, Bo Wang2, Zhen Cai1 and JingSong He1*
Abstract Background: Multiple myeloma (MM) is a type of hematological malignancy with significant heterogeneity in clinical features and prognosis. Cytogenetic abnormalities are the major factors affecting patient outcomes. Studies have shown that immunohistochemistry (IHC)-based detection of cancer-related genes expression could be alternative indicators for the prognosis of MM. Methods: Nuclear expression of c-maf protein in the bone marrow plasma cells of 128 multiple myeloma patients were examined by IHC, and its association with the clinicopathological features of MM patients was analyzed as well. Results: Among the 128 patients, the positive rate of c-maf protein expression was up to 30.5%, which had no correlation with patient age, M protein type, Durie-Salmon staging system, the International Staging System, abnormal plasma cell ratio in the bone marrow, or the level of peripheral blood hemoglobin, serum calcium or lactate dehydrogenase. However, the c-maf-positive patients had a significantly higher rate of hypoproteinemia (p = 0.026) and higher serum β2-microglobulin levels (>2500 μg/L) (p = 0.007). Patients with negative c-maf expression had higher remission rates upon the treatment of non-bortezomib-based regimens although no effect of c-maf expression on progression-free survival or overall survival was observed. Conclusion: Patients with negative c-maf expression had higher remission rates upon the treatment of nonbortezomib-based regimens although no effect of c-maf expression on survival was observed. A further large-scale prospective study is required to verify these findings. Keywords: Multiple myeloma, c-maf, Immunohistochemistry, Therapy response, Prognosis Background Multiple myeloma (MM) is a type of monoclonal plasma cell dysplasia among hematological malignancies, often leading to renal insufficiency, bone damage, anemia, and other terminal visceral damage. MM often has a relatively long period of benign pre-disease state called ‘monoclonal gammopathy of undetermined significance’ (MGUS). Approximately 1% of patients with MGUS progress to MM every year [1, 2]. There is significant heterogeneity *Correspondence: [email protected] 1 Department of Hematology, Bone Marrow Transplantation Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China Full list of author information is available at the end of the article
in the clinical features and prognosis of MM patients. Diagnostic clinical and biochemical staging systems are commonly used in the evaluation of MM. However, MM patients at the same stage may still have different disease progression [2, 3]. Cytogenetic abnormalities have become increasingly important in prognostic risk stratification and management of MM [4–7]. Conventional karyotype analysis and fluorescence in situ hybridization (FISH) are common methods for the analysis of cytogenetic abnormalities in MM. Compared to conventional karyotype analysis, which has a real lower detection rate of abnormal karyotypes, the higher detection rate of FISH make it to be a primary approach in cytogenetic analysis [4, 8].
© The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Wei et al. Exp Hematol Oncol (2017) 6:16
However, there are many cell surface molecules and intracellular molecular markers that abnormally expressed in malignant plasma cells, which are closely related to disease prognosis [9–13]. Studies have shown that the use of immunohistochemistry (IHC) to detect the expression of cancer-related genes, such as fibroblast growth factor receptor 3 (FGFR3), the tumor suppressor gene p53, and transcription factor c-maf can be an alternative method for the prognostic analysis of MM [14– 17]. In this study, we utilized immunohistochemistry to examine the expression of the transcription factor c-maf, the cellular homolog of v-maf, in MM patients in China to retrospectively analyze its correlation with disease characteristics, treatment efficacy, and patient survival.
Methods Patients
This study began on November 15, 2016, and a total of 128 MM patients who were treated in our hospital from January 1, 2009 to May 31, 2012, including 112 newly diagnosed and 16 recurrent cases, were recruited. There were 84 males and 44 females with a median age of 60 years (ranging from 31 to 88 years). In terms of the types of M protein heavy chains, 31 cases were IgA, 6 cases were IgD, 55 cases were IgG, and 36 cases were light chain. For light chain types, 60 cases were κ-light chain and 68 cases were λ-light chain. With respect to the Durie-Salmon staging system, four cases were 1A, 10 cases were 2A, 85 cases were 3A, and 29 cases were 3B. According to the International Staging System (ISS), 17 cases were stage 1, 55 cases were stage 2, and 56 cases were stage 3. Treatment regimens
Among the 128 patients, 116 received systemic treatment and were included in the statistical analysis of therapeutic efficacies of MM treatments. Of these 116 patients, 70 received bortezomib-based combination chemotherapies, mainly including a two-drug combination regimen with bortezomib and dexamethasone (PD) or three drug combination regimens with PD and cyclophosphamide (PCD), PD and doxorubicin (PAD), and PD and thalidomide (PTD) (see our previous study [18] for the specific treatment plans). The other 46 patients received thalidomide-based regimen or traditional chemotherapy, including thalidomide together with dexamethasone and cyclophosphamide or doxorubicin, or a VAD regimen only (vindesine together with doxorubicin and dexamethasone), with a median of three courses of treatment (1–8 courses). Seven patients received autologous hematopoietic stem cell transplantation, including five cases with bortezomib treatment and two cases with non-bortezomib-based treatment.
Page 2 of 8
Immunohistochemical analysis
Anti-CD138 antibody (1:100, Serotec, Oxford, UK) was used to label the plasma cells, and anti-c-maf monoclonal antibody (Vector Laboratories, Burlingame, CA) was used for immunohistochemical analysis in this study, followed by labeling with biotin-streptavidin-horse peroxidase and NovaRed substrate development. Bone marrow biopsies were collected from all 128 MM patients for routine diagnosis or assessment of disease condition by conventional decalcification, fixation, paraffin-embedding, and 5-µm sample sectioning. After deparaffinization and heat-induced antigen retrieval of the bone marrow biopsies, anti-CD138 monoclonal antibody was used to detect the plasma cells in the bone marrow. c-maf protein expression in >20% of plasma cells in the bone marrow was defined as positive expression. Paraffin-embedded human skin biopsies were used as the positive control for c-maf immunostaining. Nonimmune mouse serum was used to replace the primary antibody as a negative control. Immunohistochemical analysis of c-maf expression was performed separately by two pathologists. For any discrepancy in diagnosis, a third pathologist was assigned to adjudicate the final diagnosis. Response criteria
In this study, the responses to different treatments were classified into five categories: complete remission, partial remission (PR), very good partial response (VGPR), stable disease (SD), and progressive disease (PD). The specific evaluation criteria were in accordance with the consensus criteria of therapeutic efficacies set forth by the International Myeloma Working Group (IMWG), 2006 [19]. The therapeutic efficacies of different treatments were evaluated every 30–60 days during the treatment period. Statistical analysis
SPSS 18.0 (SPSS Inc., Chicago, IL) software was used for statistical analysis in this study. Overall survival (OS) is defined as the time from therapy initiation to death from any cause or loss of follow-up. Progressionfree survival (PFS) refers to the time elapsed between therapy initiation and disease progression or death from any cause. Pearson’s Chi square test or Fisher’s exact test were used for the comparison of frequency distribution between different groups. Independent samples t test was used to compare the difference of mean values between two groups. Kaplan–Meier method was used for the analysis of recurrence-free survival and OS of the patients. Statistical significance was defined at p 20% plasma cells in the bone marrow and were thus categorized as c-maf-positive patients (Fig. 1). Correlation between c‑maf expression and disease characteristics of MM patients
The positive expression of c-maf was not significantly correlated with patient gender, age, M protein type, Durie-Salmon staging system, the ISS, abnormal plasma cell ratio in bone marrow, peripheral blood hemoglobin, serum calcium and lactate dehydrogenase levels, and disease stage (incidence or recurrence, p > 0.05, Table 1). However, the c-maf-positive MM patients had a higher tendency of hypoalbuminemia (χ2 = 4.971, p = 0.026) than the c-maf-negative MM patients. The serum albumin levels of 25 out of 39 c-maf-positive MM patients were lower than the normal level (35 g/L, 64.1%), while only 42.7% (n = 38 out of 89) c-maf-negative patients had hypoalbuminemia. In addition, our results showed that in MM patients, the c-maf expression in the bone marrow plasma cells was significantly correlated with the serum β2-microglobulin levels in the peripheral blood. Only two (8.0%) out of 25 MM patients with normal serum β2-microglobulin levels in the peripheral blood had positive expression of c-maf, while 37 (35.9%) out of 103 MM patients with significantly high serum β2-microglobulin levels had positive expression of c-maf (χ2 = 7.403, p = 0.007). Correlation between c‑maf expression and treatment responses of MM patients
No significant differences were found between MM patients with negative and positive expression of c-maf
Page 3 of 8
who received either bortezomib- or non-bortezomibbased regimen and the number of courses of therapy (p > 0.05). In addition, no significant differences were found between the overall response rate (ORR) to treatment (PR and above) and VGPR or better response to treatment. Our analysis of MM patients who received three and more courses of therapy showed that there was no significant difference between ORR and c-maf expression. However, the c-maf-negative MM patients displayed higher VGPR and better treatment response rates albeit statistically insignificant (77.8% vs. 58.3%, p = 0.090). Further analysis in the MM patients who received bortezomib demonstrated similar therapeutic efficacy in patients with negative and positive expression of c-maf, with 78.1 and 81.2% of MM patients achieving VGPR and better therapeutic efficacy, respectively (p = 0.800). However, among the MM patients who received nonbortezomib-based treatment, the c-maf-negative MM patients had significantly better therapeutic efficacy than the c-maf-positive MM patients, with 76.9 and 12.5% of MM patients achieving VGPR and better therapeutic efficacy, respectively (p = 0.003, Table 2). Correlation between c‑maf expression and survival of MM patients
All MM patients who received treatment at our hospital (n = 116) were followed up until December 31, 2015, with a median duration of follow-up of 42.8 months. Among them, 102 MM patients (87.9%) exhibited disease progression, including 71 c-maf-negative MM patients (88.7% of all c-maf-negative MM patients) and 31 c-mafpositive MM patients (86.1% of all c-maf-positive MM patients) who had a median PFS of 15.6 months (95% CI 13.6–17.6 months). Whereas the median PFS of the c-maf-negative MM patients was 16.8 months (95% CI 13.3–20.3), that of the c-maf-positive MM patients was
Fig. 1 c-maf immunoreactivity in multiple myeloma. a Positive reaction with a bone marrow biopsy from a myeloma patient. b Negative reaction with a bone marrow biopsy from a myeloma patient
Wei et al. Exp Hematol Oncol (2017) 6:16
Page 4 of 8
Table 1 Correlation between c-maf expression and disease characteristics of multiple myeloma patients Characteristics
All patients (n = 128)
C-maf-positive (n = 39)
C-maf-negative (n = 89)
p value
Sex, F/M
44/84
11/28
33/56
0.331
Age, years, n (%) ≤60
66 (51.6)
20 (51.3)
46 (51.7)
>60
62 (48.4)
19 (48.7)
43 (48.3)
0.966
Isotype, IgH, n (%) IgA
31 (24.2)
9 (23.1)
22 (24.7)
IgD
6 (4.7)
1 (2.6)
5 (5.6)
IgG
55 (43.0)
21 (53.8)
34 (38.2)
Light chains
36 (28.1)
8 (20.5)
28 (31.5)
0.342
Isotype, IgL, n (%) κ
60 (46.9)
17 (43.6)
43 (48.3)
λ
68 (53.1)
22 (56.4)
46 (51.7)
0.622
D–S stage, n (%) 1A + 2A
14 (10.9)
2 (5.1)
12 (13.5)
3A
85 (66.4)
30 (76.9)
55 (61.8)
3B
29 (22.7)
7 (17.9)
22 (24.7)
0.176
ISS stage, n (%) I + II
72 (56.3)
20 (51.3)
52 (58.4)
III
56 (43.8)
19 (48.7)
37 (41.6)
0.453
Alb level, n (%) ≥35 g/L
65 (50.8)
14 (35.9)
51 (57.3)
2500 μg/L
103 (80.5)
37 (94.9)
66 (74.2)
0.007
Hb, n (%) 140 × 109/L
66 (51.6)
19 (48.7)
47 (52.8)
0.488
Plt, n (%) 0.670
Calcium level, n (%) ≤2.54 mmol/L
110 (85.9)
35 (89.7)
75 (84.3)
>2.54 mmol/L
18 (14.1)
4 (10.2)
14 (15.7)
0.412
CRP level, n (%) ≤8.0 mg/L
92 (71.9)
29 (74.4)
63 (70.8)
>8.0 mg/L
36 (28.1)
10 (25.6)
26 (29.2)
0.679
LDH level, n (%) ≤250 U/L
105 (82.0)
31 (79.5)
74 (79.8)
>250 U/L
23 (18.0)
8 (20.5)
15 (20.2)
0.620
ISS international stage system, Alb albumin, β2-MG β2-microglobulin, CRP c-reactive protein, LDH lactate dehydrogenase
14.5 months (95% CI 11.8–17.2); and no significant difference was found between the two groups of patients (p = 0.658). The 3-year PFS of the c-maf-negative and c-maf-positive MM patients were 20.0 and 16.7%, respectively (Fig. 2a). Eighty MM patients died at the end of the follow-up period, including 74 cases from disease progression, four
cases from septic shock, one case from sudden cardiac death and one case from other causes of death. Among the patients who dies, 53 were c-maf-negative MM patients (66.2%) and 27 were c-maf-positive MM patients (75.0%), with a median OS of 42.6 months among the patients (95% CI 35.3–49.9 months). The median OS of c-maf-negative MM patients was 45.9 months (95% CI
Wei et al. Exp Hematol Oncol (2017) 6:16
Page 5 of 8
Table 2 Correlation between c-maf expression and treatment response of multiple myeloma patients All patients (n = 116)
C-maf-positive (n = 36)
C-maf-negative (n = 80)
p value
Therapy, n (%) Bor
70 (60.3)
22 (61.1)
48 (60.0)
Non-bor
46 (39.7)
14 (38.9)
32 (40.0)
0.910
Courses, n (%)
Experimental Hematology & Oncology Open Access
RESEARCH
Clinical implications of c‑maf expression in plasma cells from patients with multiple myeloma GuoQing Wei1, LiJun Wang2, HanJin Yang2, XiaoYan Han1, GaoFeng Zheng1, WeiYan Zheng1, Jie Sun1, JiMin Shi1, WenJun Wu1, Yi Zhao1, DongHua He1, Bo Wang2, Zhen Cai1 and JingSong He1*
Abstract Background: Multiple myeloma (MM) is a type of hematological malignancy with significant heterogeneity in clinical features and prognosis. Cytogenetic abnormalities are the major factors affecting patient outcomes. Studies have shown that immunohistochemistry (IHC)-based detection of cancer-related genes expression could be alternative indicators for the prognosis of MM. Methods: Nuclear expression of c-maf protein in the bone marrow plasma cells of 128 multiple myeloma patients were examined by IHC, and its association with the clinicopathological features of MM patients was analyzed as well. Results: Among the 128 patients, the positive rate of c-maf protein expression was up to 30.5%, which had no correlation with patient age, M protein type, Durie-Salmon staging system, the International Staging System, abnormal plasma cell ratio in the bone marrow, or the level of peripheral blood hemoglobin, serum calcium or lactate dehydrogenase. However, the c-maf-positive patients had a significantly higher rate of hypoproteinemia (p = 0.026) and higher serum β2-microglobulin levels (>2500 μg/L) (p = 0.007). Patients with negative c-maf expression had higher remission rates upon the treatment of non-bortezomib-based regimens although no effect of c-maf expression on progression-free survival or overall survival was observed. Conclusion: Patients with negative c-maf expression had higher remission rates upon the treatment of nonbortezomib-based regimens although no effect of c-maf expression on survival was observed. A further large-scale prospective study is required to verify these findings. Keywords: Multiple myeloma, c-maf, Immunohistochemistry, Therapy response, Prognosis Background Multiple myeloma (MM) is a type of monoclonal plasma cell dysplasia among hematological malignancies, often leading to renal insufficiency, bone damage, anemia, and other terminal visceral damage. MM often has a relatively long period of benign pre-disease state called ‘monoclonal gammopathy of undetermined significance’ (MGUS). Approximately 1% of patients with MGUS progress to MM every year [1, 2]. There is significant heterogeneity *Correspondence: [email protected] 1 Department of Hematology, Bone Marrow Transplantation Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China Full list of author information is available at the end of the article
in the clinical features and prognosis of MM patients. Diagnostic clinical and biochemical staging systems are commonly used in the evaluation of MM. However, MM patients at the same stage may still have different disease progression [2, 3]. Cytogenetic abnormalities have become increasingly important in prognostic risk stratification and management of MM [4–7]. Conventional karyotype analysis and fluorescence in situ hybridization (FISH) are common methods for the analysis of cytogenetic abnormalities in MM. Compared to conventional karyotype analysis, which has a real lower detection rate of abnormal karyotypes, the higher detection rate of FISH make it to be a primary approach in cytogenetic analysis [4, 8].
© The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Wei et al. Exp Hematol Oncol (2017) 6:16
However, there are many cell surface molecules and intracellular molecular markers that abnormally expressed in malignant plasma cells, which are closely related to disease prognosis [9–13]. Studies have shown that the use of immunohistochemistry (IHC) to detect the expression of cancer-related genes, such as fibroblast growth factor receptor 3 (FGFR3), the tumor suppressor gene p53, and transcription factor c-maf can be an alternative method for the prognostic analysis of MM [14– 17]. In this study, we utilized immunohistochemistry to examine the expression of the transcription factor c-maf, the cellular homolog of v-maf, in MM patients in China to retrospectively analyze its correlation with disease characteristics, treatment efficacy, and patient survival.
Methods Patients
This study began on November 15, 2016, and a total of 128 MM patients who were treated in our hospital from January 1, 2009 to May 31, 2012, including 112 newly diagnosed and 16 recurrent cases, were recruited. There were 84 males and 44 females with a median age of 60 years (ranging from 31 to 88 years). In terms of the types of M protein heavy chains, 31 cases were IgA, 6 cases were IgD, 55 cases were IgG, and 36 cases were light chain. For light chain types, 60 cases were κ-light chain and 68 cases were λ-light chain. With respect to the Durie-Salmon staging system, four cases were 1A, 10 cases were 2A, 85 cases were 3A, and 29 cases were 3B. According to the International Staging System (ISS), 17 cases were stage 1, 55 cases were stage 2, and 56 cases were stage 3. Treatment regimens
Among the 128 patients, 116 received systemic treatment and were included in the statistical analysis of therapeutic efficacies of MM treatments. Of these 116 patients, 70 received bortezomib-based combination chemotherapies, mainly including a two-drug combination regimen with bortezomib and dexamethasone (PD) or three drug combination regimens with PD and cyclophosphamide (PCD), PD and doxorubicin (PAD), and PD and thalidomide (PTD) (see our previous study [18] for the specific treatment plans). The other 46 patients received thalidomide-based regimen or traditional chemotherapy, including thalidomide together with dexamethasone and cyclophosphamide or doxorubicin, or a VAD regimen only (vindesine together with doxorubicin and dexamethasone), with a median of three courses of treatment (1–8 courses). Seven patients received autologous hematopoietic stem cell transplantation, including five cases with bortezomib treatment and two cases with non-bortezomib-based treatment.
Page 2 of 8
Immunohistochemical analysis
Anti-CD138 antibody (1:100, Serotec, Oxford, UK) was used to label the plasma cells, and anti-c-maf monoclonal antibody (Vector Laboratories, Burlingame, CA) was used for immunohistochemical analysis in this study, followed by labeling with biotin-streptavidin-horse peroxidase and NovaRed substrate development. Bone marrow biopsies were collected from all 128 MM patients for routine diagnosis or assessment of disease condition by conventional decalcification, fixation, paraffin-embedding, and 5-µm sample sectioning. After deparaffinization and heat-induced antigen retrieval of the bone marrow biopsies, anti-CD138 monoclonal antibody was used to detect the plasma cells in the bone marrow. c-maf protein expression in >20% of plasma cells in the bone marrow was defined as positive expression. Paraffin-embedded human skin biopsies were used as the positive control for c-maf immunostaining. Nonimmune mouse serum was used to replace the primary antibody as a negative control. Immunohistochemical analysis of c-maf expression was performed separately by two pathologists. For any discrepancy in diagnosis, a third pathologist was assigned to adjudicate the final diagnosis. Response criteria
In this study, the responses to different treatments were classified into five categories: complete remission, partial remission (PR), very good partial response (VGPR), stable disease (SD), and progressive disease (PD). The specific evaluation criteria were in accordance with the consensus criteria of therapeutic efficacies set forth by the International Myeloma Working Group (IMWG), 2006 [19]. The therapeutic efficacies of different treatments were evaluated every 30–60 days during the treatment period. Statistical analysis
SPSS 18.0 (SPSS Inc., Chicago, IL) software was used for statistical analysis in this study. Overall survival (OS) is defined as the time from therapy initiation to death from any cause or loss of follow-up. Progressionfree survival (PFS) refers to the time elapsed between therapy initiation and disease progression or death from any cause. Pearson’s Chi square test or Fisher’s exact test were used for the comparison of frequency distribution between different groups. Independent samples t test was used to compare the difference of mean values between two groups. Kaplan–Meier method was used for the analysis of recurrence-free survival and OS of the patients. Statistical significance was defined at p 20% plasma cells in the bone marrow and were thus categorized as c-maf-positive patients (Fig. 1). Correlation between c‑maf expression and disease characteristics of MM patients
The positive expression of c-maf was not significantly correlated with patient gender, age, M protein type, Durie-Salmon staging system, the ISS, abnormal plasma cell ratio in bone marrow, peripheral blood hemoglobin, serum calcium and lactate dehydrogenase levels, and disease stage (incidence or recurrence, p > 0.05, Table 1). However, the c-maf-positive MM patients had a higher tendency of hypoalbuminemia (χ2 = 4.971, p = 0.026) than the c-maf-negative MM patients. The serum albumin levels of 25 out of 39 c-maf-positive MM patients were lower than the normal level (35 g/L, 64.1%), while only 42.7% (n = 38 out of 89) c-maf-negative patients had hypoalbuminemia. In addition, our results showed that in MM patients, the c-maf expression in the bone marrow plasma cells was significantly correlated with the serum β2-microglobulin levels in the peripheral blood. Only two (8.0%) out of 25 MM patients with normal serum β2-microglobulin levels in the peripheral blood had positive expression of c-maf, while 37 (35.9%) out of 103 MM patients with significantly high serum β2-microglobulin levels had positive expression of c-maf (χ2 = 7.403, p = 0.007). Correlation between c‑maf expression and treatment responses of MM patients
No significant differences were found between MM patients with negative and positive expression of c-maf
Page 3 of 8
who received either bortezomib- or non-bortezomibbased regimen and the number of courses of therapy (p > 0.05). In addition, no significant differences were found between the overall response rate (ORR) to treatment (PR and above) and VGPR or better response to treatment. Our analysis of MM patients who received three and more courses of therapy showed that there was no significant difference between ORR and c-maf expression. However, the c-maf-negative MM patients displayed higher VGPR and better treatment response rates albeit statistically insignificant (77.8% vs. 58.3%, p = 0.090). Further analysis in the MM patients who received bortezomib demonstrated similar therapeutic efficacy in patients with negative and positive expression of c-maf, with 78.1 and 81.2% of MM patients achieving VGPR and better therapeutic efficacy, respectively (p = 0.800). However, among the MM patients who received nonbortezomib-based treatment, the c-maf-negative MM patients had significantly better therapeutic efficacy than the c-maf-positive MM patients, with 76.9 and 12.5% of MM patients achieving VGPR and better therapeutic efficacy, respectively (p = 0.003, Table 2). Correlation between c‑maf expression and survival of MM patients
All MM patients who received treatment at our hospital (n = 116) were followed up until December 31, 2015, with a median duration of follow-up of 42.8 months. Among them, 102 MM patients (87.9%) exhibited disease progression, including 71 c-maf-negative MM patients (88.7% of all c-maf-negative MM patients) and 31 c-mafpositive MM patients (86.1% of all c-maf-positive MM patients) who had a median PFS of 15.6 months (95% CI 13.6–17.6 months). Whereas the median PFS of the c-maf-negative MM patients was 16.8 months (95% CI 13.3–20.3), that of the c-maf-positive MM patients was
Fig. 1 c-maf immunoreactivity in multiple myeloma. a Positive reaction with a bone marrow biopsy from a myeloma patient. b Negative reaction with a bone marrow biopsy from a myeloma patient
Wei et al. Exp Hematol Oncol (2017) 6:16
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Table 1 Correlation between c-maf expression and disease characteristics of multiple myeloma patients Characteristics
All patients (n = 128)
C-maf-positive (n = 39)
C-maf-negative (n = 89)
p value
Sex, F/M
44/84
11/28
33/56
0.331
Age, years, n (%) ≤60
66 (51.6)
20 (51.3)
46 (51.7)
>60
62 (48.4)
19 (48.7)
43 (48.3)
0.966
Isotype, IgH, n (%) IgA
31 (24.2)
9 (23.1)
22 (24.7)
IgD
6 (4.7)
1 (2.6)
5 (5.6)
IgG
55 (43.0)
21 (53.8)
34 (38.2)
Light chains
36 (28.1)
8 (20.5)
28 (31.5)
0.342
Isotype, IgL, n (%) κ
60 (46.9)
17 (43.6)
43 (48.3)
λ
68 (53.1)
22 (56.4)
46 (51.7)
0.622
D–S stage, n (%) 1A + 2A
14 (10.9)
2 (5.1)
12 (13.5)
3A
85 (66.4)
30 (76.9)
55 (61.8)
3B
29 (22.7)
7 (17.9)
22 (24.7)
0.176
ISS stage, n (%) I + II
72 (56.3)
20 (51.3)
52 (58.4)
III
56 (43.8)
19 (48.7)
37 (41.6)
0.453
Alb level, n (%) ≥35 g/L
65 (50.8)
14 (35.9)
51 (57.3)
2500 μg/L
103 (80.5)
37 (94.9)
66 (74.2)
0.007
Hb, n (%) 140 × 109/L
66 (51.6)
19 (48.7)
47 (52.8)
0.488
Plt, n (%) 0.670
Calcium level, n (%) ≤2.54 mmol/L
110 (85.9)
35 (89.7)
75 (84.3)
>2.54 mmol/L
18 (14.1)
4 (10.2)
14 (15.7)
0.412
CRP level, n (%) ≤8.0 mg/L
92 (71.9)
29 (74.4)
63 (70.8)
>8.0 mg/L
36 (28.1)
10 (25.6)
26 (29.2)
0.679
LDH level, n (%) ≤250 U/L
105 (82.0)
31 (79.5)
74 (79.8)
>250 U/L
23 (18.0)
8 (20.5)
15 (20.2)
0.620
ISS international stage system, Alb albumin, β2-MG β2-microglobulin, CRP c-reactive protein, LDH lactate dehydrogenase
14.5 months (95% CI 11.8–17.2); and no significant difference was found between the two groups of patients (p = 0.658). The 3-year PFS of the c-maf-negative and c-maf-positive MM patients were 20.0 and 16.7%, respectively (Fig. 2a). Eighty MM patients died at the end of the follow-up period, including 74 cases from disease progression, four
cases from septic shock, one case from sudden cardiac death and one case from other causes of death. Among the patients who dies, 53 were c-maf-negative MM patients (66.2%) and 27 were c-maf-positive MM patients (75.0%), with a median OS of 42.6 months among the patients (95% CI 35.3–49.9 months). The median OS of c-maf-negative MM patients was 45.9 months (95% CI
Wei et al. Exp Hematol Oncol (2017) 6:16
Page 5 of 8
Table 2 Correlation between c-maf expression and treatment response of multiple myeloma patients All patients (n = 116)
C-maf-positive (n = 36)
C-maf-negative (n = 80)
p value
Therapy, n (%) Bor
70 (60.3)
22 (61.1)
48 (60.0)
Non-bor
46 (39.7)
14 (38.9)
32 (40.0)
0.910
Courses, n (%)
